9-126693319-G-A

Position:

• chr9-126693319-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001174147.2(LMX1B):​c.737G>A​(p.Arg246Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R246P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LMX1B NM_001174147.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 9.51

Genes affected

LMX1B (HGNC:6654): (LIM homeobox transcription factor 1 beta) This gene encodes a member of LIM-homeodomain family of proteins containing two N-terminal zinc-binding LIM domains, 1 homeodomain, and a C-terminal glutamine-rich domain. It functions as a transcription factor, and is essential for the normal development of dorsal limb structures, the glomerular basement membrane, the anterior segment of the eye, and dopaminergic and serotonergic neurons. Mutations in this gene are associated with nail-patella syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001174147.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-126693319-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 812901.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946
• PP5: Variant 9-126693319-G-A is Pathogenic according to our data. Variant chr9-126693319-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 498798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LMX1B	NM_001174147.2	c.737G>A	p.Arg246Gln	missense_variant	4/8	ENST00000373474.9
LMX1B	NM_001174146.2	c.737G>A	p.Arg246Gln	missense_variant	4/8
LMX1B	NM_002316.4	c.737G>A	p.Arg246Gln	missense_variant	4/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LMX1B	ENST00000373474.9	c.737G>A	p.Arg246Gln	missense_variant	4/8	1	NM_001174147.2	P4
LMX1B	ENST00000355497.10	c.737G>A	p.Arg246Gln	missense_variant	4/8	1
LMX1B	ENST00000526117.6	c.737G>A	p.Arg246Gln	missense_variant	4/8	1		A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1444634 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 717430

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 04, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 10, 2022	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LMX1B protein function. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LMX1B function (PMID: 24042019, 28059119). ClinVar contains an entry for this variant (Variation ID: 498798). This missense change has been observed in individuals with focal segmental glomerulosclerosis (PMID: 23687361, 26560070, 28059119). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 246 of the LMX1B protein (p.Arg246Gln). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2023	Published functional studies demonstrate this variant partially impairs transcriptional activity, indicating haploinsufficiency (Isojima et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26560070, 28059119, 31328266, 24042019, 32791958, 33725694, 32356190, 32774956, 23891399, 28844315, 29246420, 28780565, 27450397, 30295827, 30647093, 29127259, 23687361, 28204945) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Sep 06, 2023	- -

Nail-patella syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000498798, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (, PS3_S). A different missense change at the same codon has been reported to be associated with LMX1B related disorder (ClinVar ID: VCV000812901, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.908, 3CNET: 0.933, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000000, PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	research	Molecular Biology Laboratory, Fundació Puigvert	Feb 01, 2020	- -

Nail-patella-like renal disease Pathogenic:2

Pathogenic, no assertion criteria provided	research	Department of Traditional Chinese Medicine, Fujian Provincial Hospital	-	We identified the LMX1B mutation in a young man with nephrotic syndrome who had no clinical symptoms other than renal, and the mutation site was found to be pathogenic according to the ACMG guidelines as it corresponded to PS3 (Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product)+PS4_Supporting (The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls)+PM2 (Absent from controls in Exome Sequencing Project, 1000 Genomes or ExAC)+PP1_Strong (Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease)+PP3 (Multiple lines of computational evidence support a deleterious effect on the gene or gene product). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 21, 2022	- -

Nephrotic syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Sydney Genome Diagnostics, Children's Hospital Westmead	Apr 18, 2014	This individual is heterozygous for a known pathogenic variant, c.737G>A p.(Arg246Gln) in the LMX1B gene. This variant is located in the homeobox domain of the LMX1B gene and occurs in a highly conserved amino acid residue. Originally described in a patient with nail patella syndrome (NPS) (OMIM# 602575); however, more recent reports have described this variant in multiple families with glomerular pathologies, including isolated FSGS, Nail-Patella-like Renal Disease (NPLRD) and Steroid resistant nephrotic syndrome (Boyer et al, J Am Soc Nephrol 24 (2013): 1216-1222; Hall et al, Sci Rep (2017) 7:39933). This variant is considered to be pathogenic according to the ACMG guidelines. -
Likely pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	Nov 10, 2017	- -

LMX1B-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 2024

The LMX1B c.737G>A variant is predicted to result in the amino acid substitution p.Arg246Gln. This variant has been repeatedly reported to be causative for LMX1B-related glomerulopathy (see for example, reported as de novo at Supplementary Table 2 of Domingo-Gallego et al. 2021. PubMed ID: 33532864; Boyer et al. 2013. PubMed ID: 23687361; Isojima et al. 2014. PubMed ID: 24042019; Konomoto et al. 2016. PubMed ID: 26560070; Hall et al. 2017. PubMed ID: 28059119). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

Nail-patella syndrome;C0403548:Nail-patella-like renal disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 17, 2022

- -

Inherited focal segmental glomerulosclerosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Mar 02, 2023

This sequence change in LMX1B is predicted to replace arginine with glutamine at codon 246, p.(Arg246Gln). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the homeobox domain. There is a small physicochemical difference between arginine and glutamine. This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been reported in probands/families with focal segmental glomerulosclerosis without extrarenal involvement or unspecified glomerulopathy, including at least one individual where the variant was identified as a de novo occurrence with unconfirmed parental relationships. It also segregates with kidney disease in multiple families (PMID: 23687361, 24042019, 28059119, 32791958, 32356190, 33532864). In vitro assays of LMX1B transcriptional activity in mammalian cell lines showed partially impaired transcriptional activity suggesting the variant may have dominant negative and haploinsufficiency effects (PMID: 24042019, 28059119). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (5/6 algorithms). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PP1_Strong, PS4_Moderate, PM6, PS3_Supporting, PM2_Supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	.;D;.;D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.9	D;D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.86
MutPred		0.77		.;.;.;Gain of ubiquitination at K220 (P = 0.028);
MVP		0.95
MPC		1.8
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.84
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1191455921; hg19: chr9-129455598;